Project Summary Sepsis, defined as life-threatening organ dysfunction due to a dysregulated immune host response to infection, is a major problem in resource-limited settings. The global burden of sepsis approaches nearly 19 million cases per year, the vast majority of which occur in low- and middle-income countries, and causes 5.3 million deaths annually worldwide. Unfortunately, there is limited knowledge on how to treat sepsis in resource-limited settings and the data that exist often contradict findings from studies in well-resourced environments. Recent clinical trials have found that early fluid resuscitation, an intervention that has been shown repeatedly to reduce mortality from sepsis in the United States, was associated with increased mortality in sub-Saharan Africa. The reason for this contradictory finding is unknown. The objective of this proposal is to better understand this discrepancy. The central hypothesis of this proposal is that the development of pulmonary edema mediates the causal relationship between early fluid resuscitation and mortality in patients with sepsis in resource-limited settings. In the United States and other resource-replete environments, septic patients who develop respiratory failure as a consequence of pulmonary edema can be supported with invasive mechanical ventilation. However, in resource-limited settings with scarce or no access to mechanical ventilation, the development of respiratory failure is associated with a very high mortality. Although plausible, no study to date has demonstrated the link between fluid resuscitation, pulmonary edema, and mortality in resource-limited settings. To do so, this proposal describes the novel use of lung ultrasonography to detect pulmonary edema in a cohort of adult patients admitted for sepsis at the Queen Elizabeth Central Hospital in Blantyre, Malawi. The M-PulSe Study will test whether the volume of intravenous fluid administered predicts the development of pulmonary edema in patients with sepsis (Specific Aim 1), and whether pulmonary edema is associated with increased in-hospital mortality (Specific Aim 2). The results from this study may point the way to designing an ultrasound-guided fluid resuscitation strategy for patients with sepsis which may have broad applicability to the management of sepsis worldwide. Furthermore, this study serves as a platform for training Dr. Richard Wang, a pulmonary and critical care fellow at the University of California, in the conduct of high-quality, patient-oriented clinical research. This grant provides Dr. Wang with the support necessary to acquire the knowledge and skills to become an independent clinical investigator and a leader in global health.